Glycogen synthase kinase-3 is required for axon growth and development

Glycogen Synthase Kinase-3 (GSK-3) is a critical downstream regulator in multiple signaling pathways including neurotrophin/PI3K and Wnt/[beta]-catenin pathways. GSK-3 signal has been strongly implicated in the regulation of neuronal polarity and axon growth in vitro. However, how GSK-3 is regulated and whether it is required for mammalian nervous system development is unknown. Here, I assessed the role of Par6 signaling in the regulation of GSK-3 activity and NGF-induced axon growth. My results show that Par6 is required for GSK-3 phosphorylation and inhibition. Elimination of Par6 inhibits NGF-induced axon growth. We have also generated nervous system specific GSK-3 knockout mice. By studying GSK-3 null cortical neurons, my results show that GSK-3 is required for axon growth in vivo and the deletion of GSK-3 mainly affects the microtubule dynamics which prevents the axon growth. We conclude that GSK-3 is a key regulator of axon growth and development both in vivo and in vitro

The Adenomatous Polyposis Coli Protein Is an Essential Regulator of Radial Glial Polarity and Construction of the Cerebral Cortex

Radial glia are highly polarized cells that serve as neuronal progenitors and as scaffolds for neuronal migration during construction of the cerebral cortex. How radial glial cells establish and maintain their morphological polarity is unknown. Using conditional gene targeting in mice, we demonstrate that Adenomatous Polyposis Coli (APC) serves an essential function in the maintenance of polarized radial glial scaffold during brain development. In the absence of APC, radial glial cells lose their polarity and responsiveness to the extracellular polarity maintenance cues, such as neuregulin-1. Elimination of APC further leads to marked instability of the radial glial microtubule cytoskeleton. The resultant changes in radial glial function and loss of APC in radial glial progeny lead to defective generation and migration of cortical neurons, severely disrupted cortical layer formation, and aberrant axonal tract development. Thus APC is an essential regulator of radial glial polarity and is critical for the construction of cerebral cortex in mammals

GSK-3 is a master regulator of neural progenitor homeostasis

The development of the brain requires the exquisite coordination of progenitor proliferation and differentiation to achieve complex circuit assembly. It has been suggested that glycogen synthase kinase 3 (GSK-3) acts as an integrating molecule for multiple proliferation and differentiation signals because of its essential role in the RTK, Wnt and Shh signaling pathways. We created conditional mutations that deleted both the α and β forms of GSK-3 in mouse neural progenitors. GSK-3 deletion resulted in massive hyperproliferation of neural progenitors along the entire neuraxis. Generation of both intermediate neural progenitors and postmitotic neurons was markedly suppressed. These effects were associated with the dysregulation of β-catenin, Sonic Hedgehog, Notch and fibroblast growth factor signaling. Our results indicate that GSK-3 signaling is an essential mediator of homeostatic controls that regulate neural progenitors during mammalian brain development

Influence Pathway Discovery on Social Media

This paper addresses influence pathway discovery, a key emerging problem in today's online media. We propose a discovery algorithm that leverages recently published work on unsupervised interpretable ideological embedding, a mapping of ideological beliefs (done in a self-supervised fashion) into interpretable low-dimensional spaces. Computing the ideological embedding at scale allows one to analyze correlations between the ideological positions of leaders, influencers, news portals, or population segments, deriving potential influence pathways. The work is motivated by the importance of social media as the preeminent means for global interactions and collaborations on today's Internet, as well as their frequent (mis-)use to wield influence that targets social beliefs and attitudes of selected populations. Tools that enable the understanding and mapping of influence propagation through population segments on social media are therefore increasingly important. In this paper, influence is measured by the perceived ideological shift over time that is correlated with influencers' activity. Correlated shifts in ideological embeddings indicate changes, such as swings/switching (among competing ideologies), polarization (depletion of neutral ideological positions), escalation/radicalization (shifts to more extreme versions of the ideology), or unification/cooldown (shifts towards more neutral stances). Case-studies are presented to explore selected influence pathways (i) in a recent French election, (ii) during political discussions in the Philippines, and (iii) for some Russian messaging during the Russia/Ukraine conflict.Comment: This paper is accepted by IEEE CIC as an invited vision pape